Comparison of twice-daily inhaled ciclesonide and fluticasone propionate in patients with moderate-to-severe persistent asthma
Introduction
Inhaled corticosteroids (ICS) are first-line therapy for all severities of persistent asthma [1], [2]. Some of the early molecules in this class, although still in use, have been superseded by molecules with greater efficacy, longer duration of action, more convenient formulations and more advantageous safety profiles. The ideal ICS is characterized by high local anti-inflammatory efficacy combined with a fast metabolic inactivation to avoid systemic effects. Although at low doses there may appear to be little to choose between the ICS in terms of therapeutic index, a large proportion of patients require moderate or high doses to gain control of their asthma, and in these patients the safety profile of the ICS assumes greater relevance [3], [4], [5], [6], [7], [8].
Fluticasone propionate is an ICS considered to have excellent local efficacy in the lower airway, and has been shown to be highly effective when given both alone and in combination with long-acting β2-agonists (LABAs). Other favourable features are a high first-pass metabolism, which ensures that the majority of absorbed corticosteroid is inactivated by the liver. In spite of this, it has been associated with adrenocortical suppression, especially when given in high and excessive doses [5], and rare examples of adrenocortical crisis in children resulting from its use have been described. In addition, twice-daily dosing with fluticasone propionate has been shown to provide better clinical results than a once-daily regimen [9], [10], and it is not approved for once-daily dosing.
Ciclesonide, a new class of ICS that is currently available in a number of countries, has several favourable features. These include high potency and prolonged duration of action, making it suitable for once-daily administration in the majority of patients [11], [12], [13], and a very favourable therapeutic index. Ciclesonide is a prodrug and is converted to the active metabolite, desisobutyryl-ciclesonide, in the lungs by airway-specific esterases [14]; the active metabolite has high affinity for the glucocorticoid receptor (an approximate 100-fold increase compared with the parent compound) [15]. This reduces the potential for local side effects in the oropharynx and for absorption of corticosteroid from the intestinal tract. Other features that contribute to its high-level therapeutic ratio are low oral deposition (the result of its delivery as a solution propelled by hydrofluoroalkane [HFA] in a mist of smaller particle size than the usual chlorofluorocarbon pressurized metered-dose inhalers [MDIs]), as well as high protein binding [16] and first-pass metabolism by the liver [17], both of which reduce the systemic bioavailability of any drug that is absorbed. Results of an in vivo animal study suggest that the duration of action of ciclesonide may be attributable to its lipophilicity and the formation of lipid conjugates in the lung [18].
The efficacy of ciclesonide has been compared with that of fluticasone propionate in a number of studies and over a range of doses [19], [20], [21]. For example, ciclesonide 160 μg once daily has been shown to provide comparable results to fluticasone propionate 88 μg twice daily at improving lung function and asthma symptoms, and in reducing rescue medication use in patients with mild-to-moderate persistent asthma [19]. A dose of 320 μg once daily also showed similar efficacy to that of fluticasone propionate 176 μg twice daily in patients with moderate persistent asthma [20]. However, to date, no studies at higher, comparable doses in patients with moderate-to-severe persistent asthma have been reported.
For some ICS, increased dosing frequency (twice or even four-times daily) is associated with improved efficacy and, therefore, many physicians prefer to use twice-daily dosing in patients with more severe asthma (at least at the beginning of treatment). To accommodate this tendency, the current study, which set out to compare the safety and efficacy data of ciclesonide and fluticasone propionate at similar nominal daily dosing, employed twice-daily doses for both treatments. The study compared ciclesonide 640 μg/day ex-actuator and fluticasone propionate 660 μg/day ex-actuator in terms of maintaining asthma control in patients with moderate-to-severe persistent asthma.
Section snippets
Subjects
Study subjects were outpatients aged 12–75 years with a ⩾6-month history of bronchial asthma as defined by the American Thoracic Society criteria. To enter the 2-week run-in period, patients had to have been receiving fluticasone propionate 500–1000 μg/day or equivalent at a stable dose for ⩾4 weeks and had to have a forced expiratory volume in 1 s (FEV1) ⩾80% of predicted, measured at least 4 h after short-acting β2-agonists and at least 24 h after other asthma controllers. For entry into the
Results
Overall, 658 patients were enrolled and a total of 528 patients were randomized and entered the treatment period (ciclesonide 320 μg twice daily, n=255; fluticasone propionate 330 μg twice daily, n=273) (Fig. 1). All randomized patients took at least one dose of study medication and were included in the ITT and safety analyses. A total of 81 patients (ciclesonide, n=43; fluticasone propionate, n=38) terminated the study prematurely, mainly due to AEs and ‘other reasons’. In the ciclesonide and
Discussion
The current study was designed to compare equal doses (based on μg per day) of ciclesonide and fluticasone propionate, under a similar dosing regimen. As patients entering this study were previously relatively well controlled on ICS, with normal or near-normal spirometry and at least one symptom-free day per week, initial lung function values at baseline were high, and asthma symptom scores and rescue medication use were low. However, at this level of control there was room for both improvement
Acknowledgments
This study was funded and sponsored by ALTANA Pharma. The authors would like to appreciate the data management performed by Mario Lozina (ALTANA Pharma) and thank Lesley Brewer, BSc (Hons), Medicus International, for her editorial assistance. Editorial support was funded by ALTANA Pharma.
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